Genetic Variant MYBPC3:p.Ala686Thr (chr11-47339662-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000256.3(MYBPC3):c.2056G>A(p.Ala686Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A686P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0550

Publications

2 publications found

Variant links:

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

MYBPC3 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 4
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
left ventricular noncompaction 10
Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051621616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2056G>A	p.Ala686Thr	missense_variant	Exon 21 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYBPC3	ENST00000545968.6 link	c.2056G>A	p.Ala686Thr	missense_variant	Exon 21 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6 link	c.2056G>A	p.Ala686Thr	missense_variant	Exon 20 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1 link	n.2056G>A		non_coding_transcript_exon_variant	Exon 21 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000428

AC:

AN:

233590

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000590

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450812

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720580

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33308

American (AMR)

AF:

0.00

AC:

AN:

42760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25744

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39366

South Asian (SAS)

AF:

0.00

AC:

AN:

84948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106020

Other (OTH)

AF:

0.00

AC:

AN:

59938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

CardioboostCm

Benign

0.0011

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.0

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.052

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.85

L;.;.

PhyloP100

-0.055

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.63

N;.;N

REVEL

Benign

0.046

Sift

Benign

0.43

T;.;T

Sift4G

Benign

0.20

T;T;T

Vest4

0.019

MVP

0.57

MPC

0.21

ClinPred

0.043

GERP RS

-0.17

Varity_R

0.031

gMVP

0.22

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over